Zwitterionic copolymers, method of making and use on medical devices

ABSTRACT

Biocompatible copolymers are manufactured to include a zwitterionic monomer and an alkoxy acrylate monomer. The alkoxy acrylate monomer can be a 2-methoxyethyl methacrylate (MOEMA) or 2-ethoxyethyl methacrylate (EOEMA). Alternatively, the alkoxy acrylate can be 2-methoxyethyl acrylate (MOEA) or 2-ethoxyethyl acrylate (EOEA). The alkoxy acrylate monomers advantageously give the zwitterionic copolymers greater ductility, strength, and toughness while maintaining a desired amount of hydrophilicity. The improved toughness allows the zwitterionic copolymers to be processed without cross-linking, which improves the elongation properties of the zwitterionic copolymer, and reduces the risk of cracking during use.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplications Nos. 60/866,800, 60/866,802, 60/866,804, 60/866,80560/866,798, 60/866,797, 60/866,796, 60/866,792, all of which were filedon Nov. 21, 2006, and all of which are hereby incorporated by referencein their entirety. This application is related to co-pending U.S. patentapplication Ser. No. 11/942,695, entitled “Copolymers HavingZwitterionic Moieties and Dihydroxyphenyl Moieties and Medical DevicesCoated with the Copolymers” co-pending U.S. patent application Ser. No.11/942,704, entitled “Methods of Manufacturing Copolymers withZwitterionic Moieties and Dihydroxyphenyl Moieties and Use of Same”,co-pending U.S. patent application Ser. No. 11/942,705, entitled “AminoAcid Mimetic Copolymers and Medical Devices Coated with the Copolymers”,co-pending U.S. patent application Ser. No. 11/942,969, entitled“Methods for Manufacturing Amino Acid Mimetic Copolymers and Use ofSame” co-pending U.S. patent application Ser. No. 11/942,700, entitled“Copolymers Having 1-Methyl-2-Methoxyethyl Moieties”, and co-pendingU.S. patent application Ser. No. 11/942,707, entitled “Methods forManufacturing Copolymers having 1-Methyl-2-Methoxyethyl Moieties and Useof Same”, all of which were filed on Nov. 19, 2007, and all of which arehereby incorporated by reference in their entirety. Co-pending U.S.patent application Ser. No. 11/939,512, filed Nov. 13, 2007, andco-pending application Ser. No. 11/562,338, filed Nov. 21, 2006 arehereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

1. The Field of the Invention

Embodiments of the invention relate to zwitterionic copolymers. Moreparticularly, embodiments of the invention relate to copolymers thatinclude zwitterionic monomers and alkoxy acrylate monomers and methodsof making and using the copolymers.

2. The Related Technology

Implantable medical devices, including stents, can be coated withpolymers to give the implantable device beneficial properties when usedin living tissue. Implant coatings, particularly stent coatings,typically need to simultaneously fulfill many criteria. Examples ofdesirable properties for implant coating properties include: adhesion tothe implant (e.g. adhesion to stent struts) to prevent delamination;adequate elongation to accommodate implant deformation without bucklingor cracking; sufficient hardness to withstand crimping operationswithout excessive damage; sterilizability; ability to control therelease rate of a drug; biocompatibility including hemocompatibility andchronic vascular tissue compatibility; in the case of durable orpermanent coatings, the polymer needs to be sufficiently biostable toavoid biocompatibility concerns; processability (e.g. production ofstent coatings that are microns thick); reproducible and feasiblepolymer synthesis; and an adequately defined regulatory path.

Recently, polymers containing2-(methacryloyloxyethyl)-2′-(trimethylammoniumethyl)phosphate(“phosphorylcholine” or “PC”) monomers have been developed and used onimplant devices. PC containing polymers have been shown to have manybeneficial properties. For example, PC containing polymers are typicallysterilizable, biocompatible, made from commercially available reagents,have received regulatory approval for certain embodiments, and provide acontrolled drug release rate for higher molecular weight drugs.

However, PC coatings for use on implantable devices still needimprovements with regard to several properties. Specifically, existingPC copolymers lack adequate elongation properties, especially when dry.Elongation properties are needed in order to accommodate implantdeformation without coating buckling or cracking. Furthermore, PCcopolymers need improvements in polymer hardness such that they canwithstand crimping operations without excessive damage. Finally, someexisting PC containing polymers have poorly controlled drug releaserates for lower molecular weight drugs, including corticosteroids.

SUMMARY OF THE INVENTION

Embodiments of the invention relate to biocompatible copolymers thatinclude zwitterion monomers, including but not limited tophosphorylcholine methacrylate monomers. In addition to the zwitterionmonomer, the copolymers of the invention include an alkoxy acrylatemonomer. The alkoxy acrylate monomer can be a 2-methoxyethylmethacrylate (MOEMA) or a 2-ethoxyethyl methacrylate (EOEMA). In analternative embodiment, the alkoxy acrylate monomer can be2-methoxyethyl acrylate (MOEA) or 2-ethoxyethyl acrylate (EOEA).

The alkoxy acrylate monomers advantageously give the zwitterioniccopolymers greater ductility, strength, and toughness while maintaininga desired amount of hydrophilicity. The improved toughness allows thezwitterionic copolymers to be processed without cross-linking, whichimproves the elongation properties of the zwitterionic copolymer, andreduces the risk of cracking during use.

The zwitterionic copolymers can be manufactured by polymerizing azwitterionic acrylate monomer and an alkoxy acrylate monomer in apolymerization reaction. The concentration of comonomers is selected totune the hydrophilicity and glass transition temperature of theresulting thermoplastic polymer. The copolymers and terpolymers of theinvention can be advantageously manufactured to have a desired glasstransition temperature, when hydrated, to allow for good elongation anddrug eluting properties.

These and other advantages and features of the invention will becomemore fully apparent from the following description and appended claims,or may be learned by the practice of the invention as set forthhereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

To further clarify the above and other advantages and features of theinvention, a more particular description of the invention will berendered by reference to specific embodiments thereof which areillustrated in the appended drawings. It is appreciated that thesedrawings depict only typical embodiments of the invention and aretherefore not to be considered limiting of its scope. The invention willbe described and explained with additional specificity and detailthrough the use of the accompanying drawings, in which:

FIG. 1A illustrates an example of a stent coated with a zwitterioniccopolymer according to one embodiment of the invention; and

FIG. 1B is a cross-section of a strut of the stent of FIG. 1A.

FIG. 2 is a graph showing the number of platelets adhered to onto thesurface of several acrylate polymers of this invention; and

FIG. 3 is a graph of the amount of plasma protein adsorbed on thepolymers of FIG. 2.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION I. ZwitterionicCopolymer Structures

The copolymers of the invention include a zwitterion monomer (e.g.,phosphoryl choline methacrylate) and an alkoxy acrylate monomer (e.g.,MOEMA). The zwitterionic monomers typically provide goodbiocompatibility properties and the alkoxy acrylate monomers typicallyprovide polymer toughness without cross-linking. However the inventionis not limited by these benefits.

In an embodiment of the invention, the zwitterionic copolymersincorporating the alkoxy acrylate monomer have the following chemicalformula:

In the foregoing chemical formula, R₁ and R₂ are independently ahydrogen or methyl, R₃ is a zwitterionic group with a linker group of 2to 12 carbons attached to the acryl or methacryl group via an ester oramide bond, R₅ is an ethyl or a methyl, n is in a range from about 0.01to about 0.75, and m is in a range from about 0.25 to about 0.99. In analternative embodiment, n is in a range from about 0.01 to about 0.25and m is in a range from about 0.75 to about 0.99. In one embodiment,n+m=1. Unless otherwise stated, the monomers shown in the chemicalformula above and other chemical formulas herein can be in any orderwithin the copolymer molecule and the monomer linkages shown in thechemical formulas only represent that the monomers are part of the samecopolymer molecule. Furthermore, unless otherwise stated, the polymericmolecules can include monomers other than those shown in the chemicalformulas.

A. Zwitterion Monomers

The copolymers of the invention include a zwitterion group such as, butnot limited to, phosphorylcholine (PC) monomer. Phosphorylcholine is azwitterion that is analogous to the phospholipid molecules that formcell membranes in living organisms. Consequently, this molecule can beincluded in the copolymer of the invention for its biocompatibility. Thezwitterion monomer also provides water absorption, which is useful fortuning the copolymers for desired drug permeability. In an embodiment,the zwitterion copolymer includes at least about 1.0 mol % to about 50mol % of a zwitterion monomer.

Examples of suitable zwitterions include phosphorylcholine (which isalso known as phosphatidyl choline and phosphocholine), phosphorylethanolamine, phosphatidyl ethanolamine, phosphoethanolamine,phosphatidyl serine, and sulfobetaine.

In one embodiment, the zwitterionic monomer includes a zwitterionicgroup with the following general formula.

In the foregoing formula, the moieties A² and A³, which are the same ordifferent, are —O—, —S—, —NH— or a valence bond, and W⁺ is a groupcomprising an ammonium, phosphonium or sulphonium cationic group and agroup linking the anionic and cationic moieties which in one embodimentis a C₁₋₁₂-alkanediyl group. In another embodiment, the W+ is a (CH)₂⁺N(R²)₃, where R² are the same or different and each is hydrogen or C₁₋₄alkyl, and m is from 1 to 4.

Alternatively, the zwitterionic group may be a betaine group (i.e., inwhich the cation is closer to the backbone), for instance a sulpho-,carboxy- or phosphor-betaine. In an embodiment, the betaine group hasthe formula -A⁴-R³—N⁺(R⁴)₂—R⁵—V⁻, in which A⁴ is a valence bond, —O—,—S—, or —NH—; V is a carboxylate, sulphonate or phosphate diester(monovalently charged) anion; R³ is a valence bond (together with A⁴) oralkanediyl, —C(O)alkylene- or —C(O)NH alkylene; the groups R⁴ are thesame or different and each is hydrogen or alkyl of 1 to 4 carbon atomsor the groups R⁴ together with the nitrogen to which the are attachedform a heterocyclic ring of 5 to 7 atoms; and R⁵ is an alkyanediyl of 1to 20 carbon atoms, of 1 to 10 carbon atoms, or of 1 to 6 carbon atoms.

In yet another alternative embodiment, the zwitterionic group can be anamino acid moiety in which the alpha carbon atom (to which an aminegroup and the carboxylic acid group are attached) is joined through alinker group to the backbone of the copolymer. Such groups can berepresented by the following general formula.

In the foregoing formula, A⁵ is a valence bond, —O—, —S—, or —NH—; R¹⁶is a valence bond (optionally together with A⁵) or alkanediyl,—C(O)alkylene- or —C(O)NH alkylene; the groups R¹⁷ are the same ordifferent and each is hydrogen or alkyl of 1 to 4 carbon atoms.

In yet another embodiment, the zwitterion-including monomer has thegeneral formula YBX, wherein B is a straight or branched alkylene(alkanediyl), alkyleneoxaalkylene or alkylene oligo-oxaalkylene chainoptionally including one or more fluorine atoms up to and includingperfluorinated chains or, if X or Y include a terminal carbon atombonded to B, a valence bond; X is a zwitterionic group; and Y is anethylenically unsaturated polymerizable group.

B. Alkoxy Acrylate Monomers

The zwitterionic copolymers also include alkoxy acrylate monomers. Forpurposes of this invention, the term “acrylate monomer” includesmethacrylates.

The alkoxy acrylate monomer can be 2-methoxyethyl methacrylate (MOEMA)2-ethoxyethyl methacrylate (EOEMA), 2-methoxyethyl acrylate (MOEA), or2-ethoxyethyl acrylate (EOEA).

The structures of MOEMA and EOEMA, are shown below.

These monomers can be incorporated into the zwitterionic copolymers ofthe invention to give the copolymer the desired ductility, strength, andtoughness without requiring cross-linking. The MOEMA or EOEMA monomersprovide the increased ductility, strength, and toughness necessary forforming a copolymer that is not cross-linked, while maintaining asuitable level of biocompatibility and drug permeability. Because thezwitterionic copolymers are not cross-linked they have improvedelongation properties as compared to existing zwitterionic polymers,especially when dry.

One useful attribute of MOEMA and EOEMA is their effect on glasstransition temperatures. The homopolymer of MOEMA has a glass transitiontemperature (T_(g)) of 16° C. (the T_(g) for EOEMA is slightly lower).The glass transition temperatures of MOEMA and EOEMA are useful fordesigning copolymers with a glass transition temperature less than about37° C. (i.e. body temperature) when hydrated.

Copolymers according to the invention that have a T_(g) less than 37° C.are advantageous because they can be elastic at body temperature. Inaddition, the intermediate T_(g) of MOEMA and EOEMA is desirable becauseit is sufficiently high so as to impart good mechanical strength to thePC copolymer at biological temperatures.

The T_(g) of the dry polymer can also be tuned to within a desirablerange. In one embodiment, the range is from about −30° C. to about 100°C. This range of dry T_(g)'s enables the coating to be adjusted to atemperature above the polymer T_(g) in order to avoid coating damageduring the deformation involved in crimping. It also allows atemperature to be used during the heat and pressure process used todeform a catheter balloon into the stent, which is above the T_(g) ofthe catheter balloon.

Another benefit of the alkoxy acrylate monomers is their greaterhydrophobicity compared to zwitterions. Consequently, the alkoxyacrylate monomers offset some of the hydrophilicity of the zwitterionmonomer, thereby reducing water swelling. Controlling the degree ofwater swelling is necessary to avoid the need for cross-linking, toprovide for a controlled release of medium to low molecular weight drugsand facilitates the manufacture of copolymers with desired elasticity.

As shown in the chemical structures of MOEMA and EOEMA, these monomershave an ether linkage in the alkoxy group. Although MOEMA and EOEMA aremore hydrophobic than the zwitterion monomer, the ether linkage providesa degree of hydrophilicity. The ether linkage makes MOEMA and EOEMA morehydrophilic than alkyl methacrylates, for example. The intermediatehydrophilicity of MOEMA and EOEMA provides greater ability toincorporate the MOEMA or EOEMA into zwitterionic copolymers whileproperly controlling water swelling and thus drug permeability.

Another benefit of the MOEMA and EOEMA monomers is their anti-foulingproperties. Considering the chemical structures of MOEMA and EOEMA, onecan see that these compounds include the smallest PEG-type grouppossible: a single alkyloxyethyl group. PEG is known for its non-foulingand protein repelling properties. The analogous structure with PEG isthe reason for the biocompatibility of MOEMA and EOEMA. The foregoingbenefits can also be provided by MOEA and EOEA.

Studies on monomers analogous to the methoxy acrylate monomers of theinvention illustrate the biocompatibility of the methoxy acrylatemonomers in living tissue. For example, 2-methoxyethyl acrylate (MEA)has been extensively studied for blood contacting applications. Tanakaet al. compared the thrombogenicity of poly(2-methoxyethyl acrylate)(PMEA), poly(2-hydroxyethyl methacrylate) (PHEMA), poly(2-hydroxyethylacrylate) (PHEA), and other alkyl methacrylates (Tanaka M., et al.,Biomaterials 21 (2000) 1471-1481. Several measures of in vitrohemocompatibility, including human platelet adhesion, changes inplatelet morphology, total absorbed protein from human plasma, amount ofabsorbed BSA, adsorbed human fibrinogens, and changes in proteinconformation by circular dichroism were measured. In the graphs shown inFIG. 2 and FIG. 3 are data showing the number of platelets adhered andthe total amount of plasma protein adsorbed onto the polymer in vitro.

As can be seen, the PMEA coating is the most hemocompatible of thepolymers tested. Kocakular et al. investigated the blood compatibilityof PMEA coated extracorporeal circuits (Kocakular M., et al., JBioactive and Compatible Polymers Vol. 17, September 2002, p. 343).Hollow fiber oxygenators coated with PMEA were evaluated during twentyclinical procedures requiring cardiopulmonary bypass. The operationswere compared to twenty operations with uncoated hollow fiberoxygenators. PMEA coatings were found to reduce both platelet adhesionand fibrinogen/albumin absorption. A coating of PEMA, known as the XCoating®, is used in the CAPIOX RX blood oxygenator sold by Terumo.

EOEMA is also known to be biocompatible as indicated by its use incontact lenses. The foregoing studies and uses support the conclusionthat the zwitterionic copolymers that include MOEMA or EOEMA (oralternatively MOEA or EOEA), are biocompatible and suitable for use asdrug eluting coatings for implant devices such as, but not limited to,stents.

II. Zwitterionic Terpolymers Including Alkyl Acrylates

In an alternative embodiment, the zwitterionic copolymer includes analkyl acrylate co-monomer in addition to the alkoxy acrylate monomer andthe zwitterion acrylate monomer. The combination of zwitterionicacrylate monomer, alkoxy acrylate monomer, and alkyl acrylate monomersallows for superior tunability in the mechanical and water swellingproperties of the copolymers. An example of a chemical formula of aterpolymer according to one embodiment of the invention is as follows.

In the foregoing chemical formula, R₁, R₂, and R₄ are independently ahydrogen or methyl; R₃ is a zwitterionic group with a linker group of 2to 12 carbons attached to the acryl or methacryl group via an ester oramide bond; R₅ is a ethyl or methyl; R₆ is a straight chain, branched,unsaturated or cyclic hydrocarbon of one to sixteen carbon atoms; n isin a range from about 0.01 to about 0.75; m is in a range from about 0.1to about 0.99; o is in a range from about 0.1 to about 0.99; andm+n+o=1.

Examples of suitable groups for R₆ include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,2-ethyl-hexyl, n-hexyl, cyclohexyl, n-hexyl, isobornyl, andtrimethylcyclohexyl groups.

In one embodiment, the alkyl acrylate monomer is n-butyl methacrylate,which, in its homopolymer form, is referred to as poly(n-butylmethacrylate) (PBMA). The PBMA homopolymer is an amorphous,thermoplastic polymer that possesses many properties desired for animplant device coating and particularly stent coatings. PBMA has a T_(g)in the range of 20-25° C. (depending on molecular weight) (J. Brandrup,E. H. Immergut, E. A. Grulke “Polymer Handbook,” 4th Edition, John Wiley& Sons, 1999). PBMA is also has a combination of a non-polar butyl tail,a polar ester group, and some limited hydrogen bonding ability via thecarbonyl oxygen. This combination of a low T_(g) and different chemicalmoieties allows for optimization of its non-covalent adhesiveinteractions. PBMA adheres well to metal surfaces and is very biostableas it has an all carbon backbone consisting of alternating secondary andquaternary carbons. Ester groups can be hydrolyzed, but the ester groupof PBMA is alpha to a tertiary carbon that makes the carbonyl carbonsterically hindered such that hydrolysis of the ester is difficult. PBMAis also known to be biocompatible with respect to vascular tissue andhemocompatibility.

With regard to mechanical integrity, PBMA can have good elongation dueto its T_(g) below body temperature. PBMA is quite hydrophobic, withwater absorption of only 0.4% (T. R, Aslamazova. et al., PolymerScience, USSR, Vol. 25. No. 6, pp. 1484-1490, 1933). Terpolymersincluding a zwitterionic monomer, an alkoxy acrylate monomer, and PBMAcan possess desired water swelling, mechanical strength, and elongation,without cross-linking.

III. Methods of Manufacturing

The method of manufacturing the copolymers of the invention includesreacting a zwitterionic acrylate monomer with an alkoxy acrylatemonomer. The copolymers can be synthesized using free radicalpolymerization, atom transfer radical polymerization, cationicpolymerization, anionic polymerization, iniferter polymerization, orother suitable reactions.

Free radical polymerization is carried out in a solvent using aninitiator. Examples of solvents suitable for carrying out thepolymerization reaction include alcoholic solvents such as, but notlimited to, methanol, ethanol, and isopropanol. Examples of suitableinitiators for carrying out the polymerization reaction includeperoxides, such as, but not limited to, benzoyl peroxide, and azocompounds. A specific example of a suitable initiator is2,2′-azo-bis(2-methylpropionitrile). Those skilled in the art arefamiliar with the conditions for carrying out the foregoingpolymerization reactions and other similar polymerization reactionssuitable for yielding the copolymers of the invention.

An alternate path to synthesizing the zwitterionic copolymers includescopolymerizing one or more monomers to form an intermediate polymer andcoupling the alkoxy group and/or the zwitterion group to theintermediate polymer. In one embodiment, the intermediate polymer can besynthesized from an acrylic acid monomer or a methacrylic acid monomerand optionally the zwitterion acrylate monomer, the alkoxy acrylatemonomer, and/or the alkyl acrylate monomer. The acrylic acid ormethacrylic acid monomers provide carboxyl groups in the intermediatepolymer where the zwitterion group, alkoxy group, or alkyl group can becoupled.

Polymerization of the monomers to form the intermediate polymer can becarried out using the polymerization techniques described above. Severalcoupling chemistries are suitable for coupling a hydroxyl or aminofunctional zwitterionic group, a hydroxyl functional alkoxy group, or ahydroxyalkyl group to the intermediate polymer, including, but notlimited to, conversion to the acid chloride or use of carbodiimides. Aparticularly facile technique uses dicyclohexyl carbodiimide (DCC) and4-(dimethylamino)pyridinium (DPTS) as described in M. Trollsas, J.Hedrick, Macromolecules 1998, 31, 4390-4395.

Yet another technique for synthesizing the copolymers begins with thehomopolymer of the alkoxy acrylate monomer. The alkoxy groups of thishomopolymer can be exchanged off by catalytic esterification to form abond between a zwitterion compound and the intermediate homopolymer. Anexample of a suitable catalyst for esterification is an organic acidcatalyst, such as, but not limited to, p-toluene sulfonic acid.

In another alternative embodiment, the zwitterion acrylate monomer canbe used to synthesize an intermediate homopolymer. The alkoxy group canthen be coupled to an intermediate zwitterion homopolymer usingtransesterification.

The zwitterionic terpolymers of the invention can also be manufacturedusing any of the foregoing alternative synthesis routes.

The zwitterionic polymers can be made mechanically robust by increasingthe polymer's number average molecular weight. The molecular weight ofthe polymer can be increased, if desired, so long as processability isnot compromised. In one embodiment, the molecular weight of the polymeris in a range from about 20K to 800K. In an alternative embodiment, themolecular weight can be in a range from 100K to 600K. If a tacky oradhesive polymer is desired the molecular weight can be in a range fromabout 2K to about 200K. A high molecular weight yields a higher ultimateelongation for the polymer, which typically improves coating integrity.For a thermoplastic polymer, high molecular weight typically yieldsbetter mechanical properties.

In one embodiment, the polymer compositions are manufactured to have adesired T_(g) when hydrated. The T_(g) of the polymer can be calculatedby knowing the amount of water absorbed and the T_(g)s derived frommeasurements of the homopolymer of the respective monomers. In anembodiment, the T_(g) is calculated using the Fox equation, which isshown below.

$\frac{1}{T_{g}^{Polymer}} = {\frac{W^{PC}}{T_{g}^{PC}} + \frac{W^{Water}}{T_{g}^{Water}} + \frac{W^{Methacrylate}}{T_{g}^{Methacrylate}}}$where:

-   -   T_(g)=Glass transition temperature of the homopolymer or pure        material.    -   T_(g) ^(water)=40° C.    -   W=Weight fraction of the components.

Once the water absorption of the polymer is known, which is usuallymeasured experimentally, the copolymer T_(g) can be estimated with thedesired target. In one embodiment the desired target T_(g) is in a rangefrom about −30° C. to about 37° C. when in the fully hydrated state. Inanother range, the T_(g) is between about 0° C. and about 37° C. whenhydrated. With a T_(g) of less than 37° C., the copolymers of theinvention will have a high degree of polymer mobility when placed invivo. This feature allows the surface of the polymer to enrich inhydrophilic monomer content, which is advantageous for biocompatibility.

In an alternative embodiment, the co-polymer is designed to have adesired T_(g) for the polymer in the dry state. In an embodiment, theT_(g) of the polymer when dry is in a range from about −30° C. to about100° C. or in an alternative range from 0° C. to about 70° C.

The biocompatibility of commercially available PC including polymers hasbeen attributed to a high mol % of PC (e.g. 23 mol % PC content forcommercially available PC1036). With a design T_(g) of less than 37° C.for the zwitterionic polymers of the invention, the polymer will have ahigh degree of polymer mobility when placed in vivo. This feature of theinvention allows the surface of the polymer to enrich in zwitterioncontent, ensuring the biocompatibility of the copolymers across a widerange of zwitterion content (e.g., 1 mol %-50 mol %).

Terpolymers of a zwitterion monomer, an alkoxy acrylate monomer and analkyl acrylate monomer can be manufactured using the same techniques asabove, with the addition of a polymerizable monomer of an alkyl acrylatemonomer. Examples of suitable alkyl acrylate monomers include ethylmethacrylate, n-butyl methacrylate, lauryl methacrylate, methylmethacrylate, isopropyl methacrylate, n-propyl methacrylate, isobutylmethacrylate, sec-butyl methacrylate, tert-butyl methacrylate, n-hexylmethacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate, phenylmethacrylate, benzyl methacrylate, isobornyl methacrylate,trimethylcyclohexyl methacrylate, n-dodecyl methacrylate, methacrylateswith pendant groups comprising up to 16 carbons, methyl acrylate, ethylacrylate, propyl acrylate, n-butyl acrylate, isobutyl acrylate,sec-butyl acrylate, n-hexyl acrylate, cyclohexyl acrylate, phenylacrylate, benzyl acrylate, styrene, alkyl substituted styrene, ethylene,propylene, 1-butene, and isobutylene.

IV. Use of Coatings on Implantable Devices

The foregoing novel polymers are suitable for use on any implantablemedical device that is compatible with zwitterion-including polymers.The copolymers can be used alone as a coating or can be combined withother polymers or agents to form a polymer coating. For example, thepolymers may be blended with poly(vinyl pyrrolidinone), poly(n-butylmethacrylate), poly(n-butyl methacrylate) copolymers, methacrylatepolymers, acrylate polymers, and/or a terpolymers of hexyl methacrylate,vinyl acetate, and vinyl pyrrolidinone.

The polymer coatings can be applied to a medical device using anytechniques known to those skilled in the art or those that may bedeveloped for applying a coating to a medical device. Examples ofsuitable techniques for applying the coating to the medical deviceinclude spraying, dip coating, roll coating, spin coating, powdercoating, and direct application by brush or needle. One skilled in theart would appreciate the many different techniques used in powdercoating and apply them to the embodiments of the invention. Thecopolymers can be applied directly to the surface of the implant device,or they can be applied over a primer or other coating material.

In one embodiment, the polymer coatings are applied to a medical deviceusing a solvent-based technique. The polymer can be dissolved in thesolvent to form a solution, which can be more easily applied to themedical device using one or more of the above mentioned techniques oranother technique. Thereafter substantially all or a portion of thesolvent can be removed to yield the polymer coating on a surface of themedical device.

Examples of suitable solvents that can be used with the copolymers ofthe invention include, but are not limited to, dimethylacetamide (DMAC),dimethylformamide (DMF), tetrahydrofuran (TWF), dimethylsulfoxide(DMSO), cyclohexanone, xylene, toluene, acetone, n-butanol, i-propanol,methyl ethyl ketone, propylene glycol monomethyl ether, methyl t-butylketone, methyl isobutyl ketone, ethyl acetate, n-butyl acetate, ethanol,methanol, chloroform, trichloroethylene, 1,1,1-trichloreoethane,methylene chloride, cyclohexane, octane, n-hexane, pentane, and dioxane.Solvent mixtures can be used as well. Representative examples of themixtures include, but are not limited to, DMAC and methanol (50:50 w/w);water, i-propanol, and DMAC (10:3:87 w/w); and i-propanol and DMAC(80:20, 50:50, or 20:80 w/w).

Examples of suitable implantable devices that can be coated with thecopolymers of the invention include coronary stents, peripheral stents,catheters, arterio-venous grafts, by-pass grafts, pacemaker anddefibrillator leads, anastomotic clips, arterial closure devices, patentforamen ovale closure devices, and drug delivery balloons. Thecopolymers are particularly suitable for permanently implanted medicaldevices.

The implantable device can be made of any suitable biocompatiblematerials, including biostable and bioabsorbable materials. Suitablebiocompatible metallic materials include, but are not limited to,stainless steel, tantalum, titanium alloys (including nitinol), andcobalt alloys (including cobalt-chromium-nickel andcobalt-chromium-tungsten alloys). Suitable nonmetallic biocompatiblematerials include, but are not limited to, polyamides, fluoropolymers,polyolefins (i.e. polypropylene, polyethylene etc.), nonabsorbablepolyesters (i.e. polyethylene terephthalate), and bioabsorbablealiphatic polyesters (i.e. homopolymers and copolymers of lactic acid,glycolic acid, lactide, glycolide, para-dioxanone, trimethylenecarbonate, ε-caprolactone, and the like, and combinations of these).

The copolymers are particularly advantageous as a coating for stents dueto their elongation properties, which allows the coated stent to becrimped and expanded without cracking the coating. The stents can becomposed of wire structures, flat perforated structures that aresubsequently rolled to form tubular structures, or cylindricalstructures that are woven, wrapped, drilled, etched or cut.

FIG. 1A shows an example stent 10 coated with a polymer includingzwitterionic monomers and alkyl acrylate monomers. Stent 10 includes agenerally tubular body 12 with a lumen. The struts of body 12 (e.g.strut 14) provide a supporting structure for coating the polymers of theinvention.

FIG. 1B illustrates a cross-section of the stent of FIG. 1A coated witha polymer coating 16 according to an embodiment of the invention. Thepolymer coating 16 can be conformal as in FIG. 1B. Alternatively, thecoating can be ablumenal, luminal, or any combination thereof. In oneembodiment, the copolymers of the invention are elastic at bodytemperatures and can therefore expand without cracking as the stentexpands during use.

The polymer coated stents of embodiments of the invention can beself-expanding or balloon expandable. The copolymer coatings of theinvention can be particularly advantageous for self expanding stents.Self expanding stents are typically restrained by a sheath that isremoved during deployment of the stent. The copolymers of the inventionhave improved mechanical strength to better withstand the frictionexerted on the polymer as the sheath is removed.

In one embodiment, a bioactive agent is associated with the coatedmedical devices of the invention. The bioactive agent can beincorporated into a base coat, top coat, mixed with the novel copolymersof the invention, and/or incorporated or otherwise applied to asupporting structure of the medical device.

The bioactive agent can have any therapeutic effect. Examples ofsuitable therapeutic properties include anti-proliferative,anti-inflammatory, antineoplastic, antiplatelet, anti-coagulant,anti-fibrin, antithrombonic, antimitotic, antibiotic, antiallergic andantioxidant properties.

Examples of suitable bioactive agents include synthetic inorganic andorganic compounds, proteins and peptides, polysaccharides and othersugars, lipids, DNA and RNA nucleic acid sequences, antisenseoligonucleotides, antibodies, receptor ligands, enzymes, adhesionpeptides, blood clot agents, including streptokinase and tissueplasminogen activator, antigens, hormones, growth factors, ribozymes,retroviral vectors, anti-proliferative agents including rapamycin(sirolimus), 40-O-(2-hydroxyethyl)rapamycin (everolimus),40-O-(3-hydroxypropyl)rapamycin, 40-O-(2-hydroxyethyoxy)ethylrapamycin,40-O-tetrazolylrapamycin (zotarolimus, ABT-578),40-epi-(N-1-tetrazolyl)-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, Biolimus A9 (biosensorsInternational, Singapore), deforolimus, AP23572 (Ariad Pharmaceuticals),paclitaxel, docetaxel, methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride, mitomycin,antiplatelet compounds, anticoagulants, antifibrin, antithrombinsincluding sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin, prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorsincluding Angiomax ä, calcium channel blockers including nifedipine,colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega3-fatty acid), histamine antagonists, lovastatin, monoclonal antibodies,nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors,suramin, serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine, nitric oxide or nitric oxide donors, super oxidedismutases, super oxide dismutase mimetic, estradiol, anticancer agents,dietary supplements including vitamins, anti-inflammatory agentsincluding aspirin, tacrolimus, dexamethasone, dexamethasone acetate,dexmethasone phosphate, momentasone, cortisone, cortisone acetate,hydrocortisone, prednisone, prednisone acetate, betamethasone,betamethasone acetate, clobetasol, cytostatic substances includingangiopeptin, angiotensin converting enzyme inhibitors includingcaptopril, cilazapril or lisinopril, antiallergic agents is permirolastpotassium, alpha-interferon, bioactive RGD, and genetically engineeredepithelial cells. Other bioactive agents which are currently availableor that may be developed in the future for use with DESs may likewise beused and all are within the scope of this invention.

The medical devices of the invention can be used in any vascular,tubular, or non-vascular structure in the body. In an embodiment, acoated stent can be used in, but is not limited to use in, neurological,carotid, coronary, aorta, renal, biliary, ureter, iliac, femoral, andpopliteal vessels.

IV. EXAMPLES

The following are specific examples of copolymers of zwitterionicmonomers and alkyl acrylate monomers. The following copolymers areuseful for coating implantable medical devices.

Example 1

Example 1 describes a copolymer of methacryloyloxyethyl phosphorylcholine and 2-methoxyethyl methacrylate.

in which,

-   -   n is in a range from about 0.01 to about 0.5; and    -   m is in the range from about 0.5 to about 0.99

Example 2

Example 2 describes a copolymer of methacryloyloxyethyl phosphorylcholine, 2-ethoxyethyl methacrylate, and n-butyl methacrylate.

in which,

-   -   n is in the range from about 0.01 to about 0.5;    -   m is in the range from about 0.01 to about 0.5; and    -   o is in the range from about 0.01 to about 0.98.

Example 3

Example 3 describes a method for manufacturing a stent using thepolymers of Examples 1 and/or 2. In a first step, a primer coating isapplied to the stent. A primer solution including between about 0.1 mass% and about 15 mass %, (e.g., about 2.0 mass %) of poly(n-butylmethacrylate) (PBMA) and the balance, a solvent mixture of acetone andcyclohexanone (having about 70 mass % of acetone and about 30 mass % ofcyclohexanone) is prepared. The solution is applied onto a stent to forma primer layer.

To apply the primer layer, a spray apparatus, (e.g., Sono-Tek MicroMistspray nozzle, manufactured by Sono-Tek Corporation of Milton, N.Y.) isused. The spray apparatus is an ultrasonic atomizer with a gasentrainment stream. A syringe pump is used to supply the coatingsolution to the nozzle. The composition is atomized by ultrasonic energyand applied to the stent surfaces. A useful nozzle to stent distance isabout 20 mm to about 40 mm at an ultrasonic power of about one watt toabout two watts. During the process of applying the composition, thestent is optionally rotated about its longitudinal axis, at a speed of100 to about 600 rpm, for example, about 400 rpm. The stent is alsolinearly moved along the same axis during the application.

The primer solution is applied to a 15 mm Triplex, N stent (availablefrom Abbott Vascular Corporation) in a series of 20-second passes, todeposit, for example, 20 μg of coating per spray pass. Between the spraypasses, the stent is allowed to dry for about 10 seconds to about 30seconds at ambient temperature. Four spray passes can be applied,followed by baking the primer layer at about 80° C. for about 1 hour. Asa result, a primer layer can be formed having a solids content of about80 μg. For purposes of this invention, “Solids” means the amount of thedry residue deposited on the stent after all volatile organic compounds(e.g., the solvent) have been removed.

In a subsequent step, a copolymer solution is prepared. The copolymersolution includes the copolymer of Examples 1 and/or Example 2. Thesolution is prepared by dissolving between about 0.1 mass % and about 15mass %, (e.g., about 2.0 mass %) of the copolymer in a solvent. Thesolvent can be a mixture of about 50 mass % ethanol and about 50 mass %n-butanol.

In a manner similar to the application of the primer layer, thecopolymer solution is applied to a stent. Twenty spray passes areperformed with a coating application of 10 μg per pass, with a dryingtime between passes of 10 seconds, followed by baking the copolymerlayer at about 60° C. for about 1 hour, to form a layer having a solidscontent between about 30 μg and 750 μg, (e.g., about 225 μg).

Example 4

Example 4 describes a method for manufacturing a drug eluting stentaccording to an embodiment of the invention. The medical device ismanufactured using the same method as in Example 3, except that insteadof the copolymer solution, a polymer-therapeutic solution is preparedand applied using the following formula.

A drug-including formulation is prepared that includes:

(a) between about 0.1 mass % and about 15 mass %, (e.g., about 2.0 mass%) of the copolymer of Example 1 and/or Example 2;

(b) between about 0.1 mass % and about 2 mass %, for example, about 1.0mass % of bioactive agent. In one embodiment, the bioactive agent isABT-578 (available from Abbott Vascular Corp. of Chicago, Ill.); and

(c) the balance, a solvent mixture including about 50 mass % of ethanoland about 50 mass % of n-butanol.

The drug-including formulation is applied to the stent in a mannersimilar to the application of the copolymer solution in Example 3. Theprocess results in the formation of a drug-polymer reservoir layerhaving a solids content between about 30 μg and 750 μg, (e.g., about 225μg), and a drug content of between about 10 μg and about 250 μg, (e.g.,about 75 μg).

The invention may be embodied in other specific forms without departingfrom its spirit or essential characteristics. The described embodimentsare to be considered in all respects only as illustrative and notrestrictive. The scope of the invention is, therefore, indicated by theappended claims rather than by the foregoing description. All changeswhich come within the meaning and range of equivalency of the claims areto be embraced within their scope.

Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein.

1. A biocompatible polymer of the chemical formula:

in which, R₁ and R₂ are independently a hydrogen or methyl; R₃ is azwitterion group having the formula:

in which A⁵ is selected from the group consisting of —O—, —S— and —NH—;R¹⁶ is selected from the group consisting of alkanediyl, —C(O)alkylene-and —C(O)NHalkylene-; the R₃ ¹⁷ groups are independently selected fromthe group consisting of hydrogen, 1 to 4 carbon atoms or, taken togetherwith the nitrogen to which they are bonded , a heterocyclic ring of 5 to7 atoms; R₅ is an ethyl or methyl; n is in an range from about 0.01 toabout 0.75; and m is in a range from about 0.25 to about 0.99.
 2. Abiocompatible polymer as in claim 1, in which R₅ is a methyl.
 3. Abiocompatible polymer as in claim 1, in which R₅ is an ethyl.
 4. Thebiocompatible polymer of claim 1, wherein R₃ is selected from the groupconsisting of phosphorylcholine, phosphorylethanolamine,phosphatidylethanolamine, phosphatidylserine, sulfobetaine andcombinations thereof.
 5. The biocompatible polymer of claim 1, whereinthe copolymer has a number average molecular weight of about 20 kD toabout 800 kD.